Compounds based on the ergoline ring system (I): ##STR1## have a surprising variety of pharmaceutical activities. For example, lysergic and isolysergic acid are 8-carboxy-6-methyl-.DELTA..sup.9 -ergolines. The amides of lysergic acid, many of which have valuable and unique pharmacologic properties, include the naturally occurring oxytocic alkaloids -- ergocornine, ergokryptine, ergonovine, ergocristine, ergosine, ergotamine etc. -- and synthetic oxytocics such as methergine as well as the synthetic hallucinogen -- lysergic acid diethylamide or LSD. The amides of 6-methyl-8-carboxyergoline, known generically as dihydroergot alkaloids, are oxytocic agents of lower potency and also lower toxicity than the ergot alkaloids themselves. Ergotamine, a .DELTA..sup.9 -ergoline, has been used in the treatment of migraine and recently, both ergocornine and 2-bromo-.alpha.-ergokryptine have been shown to be inhibitors of prolactin and of dimethylbenzanthracene (DMBA)-induced tumors in rats, according to Nagasawa and Meites, Proc. Soc. Exp'tl. Biol. Med. 135, 469 (1970) and to Heuson et al., Europ. J. Cancer, 353, (1970). (See also U.S. Pat. Nos. 3,752,888 and 3,752,814).
D-6-methyl-8-cyanomethylergoline was first prepared by Semonsky and co-workers, Coll. Czech. Chem. Commun., 33, 577 (1968), and its use in preventing pregnancy in rats was published by the same group in Nature, 221, 666 (1969). (See also U.S. Pat. No. 3,732,231). The compound was thought to interfere with the secretion of hypophysial leuteotropic hormone and the hypophysial gonadotropins. It was also suggested that the compound inhibited the secretion of prolactin. [See Seda et al., Reprod. Fert., 24, 263 (1971) and Mantle and Finn, id. 441)]. Semonsky and co-workers, Coll. Czech. Chem. Comm., 36, 220 (1971), described the preparation of D-6-methyl-8-ergolinylacetamide, a compound which is stated to have anti-fertility and anti-lactating effects on rats. The effect of these compounds in neoplastic disease is unknown.
Ergolines having a group other than methyl in the 6-position have been prepared by Fehr et al., Helv. Chim. Acta, 53, 2197 (1971) and Nakaharo et al., Chem. Pharm. Bull., 19, 2337 (1971).